N-cinnamyl - 4-(3&#39;-hydroxyphenyl) - 4-propionyl-piperidine and salts for relieving pain

ABSTRACT

ANALGESIC COMPOSITION CONTAINING AS THE ACTIVE INGREDIENT N-CINNAMYL-4-(3&#39;&#39;-HYDROXYPHENYL)-4-PROPIONYL-PIPERIDINE AND NON-TOXIC, PHARMACOLOGICALLY ACCEPTABLE ACID ADDITION SALTS THEREOF, AND METHOD OF RELIEVING PAIN IN WARM-BLOODED ANIMALS.

N-CINNAMYL 4-(3-HYDROXYPHENYL) 4-PRO- PIONYL-PIPERIDINE AND SALTS FORRELIEV- ING PAIN Herbert Merz, Ingelheim am Rhein, Germany. Kurt Freter,Beaconsfield, Quebec, Canada, and Karl Zeile, Ingelheim am Rhein,Germany, assignors to Boehringer Ingelheim GmbH, Ingelheim am Rhein,Germany No Drawing. Application Feb. 19, 1971, Ser. No. 117,121, nowPatent No. 3,708,597, which is a continuation of application Ser. No.869,955, Oct. 29, 1969, which is a continuation of application Ser. No.744,325, July 12, 1968, which is a continuation-in-part of applicationSer. No. 350,128, Mar. 6, 1964, which in turn is a continuation-in-partof application Ser. No. 177,171, Mar. 5, 1962, all now abandoned.Divided and this application Aug. 29, 1972, Ser. No. 284,603

Int. Cl. A61k 27/00 US. Cl. 424-267 3 Claims ABSTRACT OF THE DISCLOSUREAnalgesic composition containing as the active ingrediient -Ncinnamyl-4-(3-hydroxyphenyD-4propionyl-piperidine and non-toxic,pharmacologically acceptable acid addition salts thereof, and method ofrelieving pain in warm-blooded animals.

This application is a division of US. patent application Ser. No.117,121 filed Feb. 19, 1971, now US. Pat. No. 3,708,597 which in turn isa streamlined continuation of US. patent application Ser. No. 869,955filed Oct. 29, 1969, now abandoned, which in turn is a streamlinedcontinuation of US. patent application Ser. No. 744,325 filed July 12,1968, now abandoned which in turn is a continuation-in-part of copendingapplication Ser. No. 350,128, filed Mar. 6, 1964 now abandoned, which inturn is a continuation-in-part of copending application Ser. No.177,171, filed Mar. 5, 1962, now abandoned.

This invention relates toN-cinnamyl-4-(3'-hydroxyphenyl)-4-propionyl-piperidine and non-toxic,pharmacologically acceptable acid addition salts thereof, as well as tovarious methods of preparing these compounds.

More particularly, the present invention relates to N-cinnamyl-4-(3'-hydroxyphenyl)-4-propionyl-piperidine of the formula N(EHg-CH=C H-CoHs and non-toxic, pharmacologically acceptable acidaddition salts thereof.

The compound of the Formula I according to the present invention may beprepared by a number of methods which are well known in principle.However, the following methods have proved to be especiallyadvantageous:

METHOD A Reaction of 4-(3'-hydroxyphenyl)-4-propionyl-piperidine of theformula United States Patent 3,763,164 Patented Oct. 2, 1973 wherein Halis a halogen, in accordance with the following reaction formula:

The reaction is preferably performed in the presence of an inert organicsolvent and a weak base, such as sodium bicarbonate, at temperaturesbetween 50 and C. The reactants may be provided in a molar ratio of 1:1,but it is preferred to use the halide IIa in excess over thestoichiometrically required amount.

Compound II, that is, 4-(3'-hydroxyphenyl)-4-propionyl-piperidine, whichis used as one of the starting materials in this method, may itself beprepared as follows:

A m-alkoxy-benzyl-cyanide of the formula alkyl-O -CHr-CEN is condensedwith a tertiary bis-(fi-haloethyD-p-toluenesulfonyl amine of the formulaHal 5H.

Hal 511.

wherein Hal is a halogen, in the presence of a basic condensation agentto form the corresponding 4-cyano-4- derivative of the formula which isthen reacted with a Grignard reagent of the formula C H --MgHa1 whereinHal is a halogen, and then with water and ammonium chloride to form thecorresponding4-(3'-alkoxyphenyl)-4-ethylketimine-N-(p-toluenesulfonyl)-piperidine ofthe formula alkyl-O and hydrolyzing this ketimine compound, for examplewith HBr, to form the desired 4-(3'-hydroxyphenyl)4-propionyl-piperidine (II).

In the reaction of the m-alkoxy-benzyl-cyanide (1) with the bis-(18-haloethyl)-(p-toluenesulfonyl)-amine (2), powdered sodium amide ispreferably used as the basic condensation agent and the condensationreaction is most advantageously carried out in the presence of an inertorganic solvent, such as toluene, and at a temperature between 50 and200 C.

The reaction of the 4-(m-alkoxyphenyl)-4-cyano-N-(ptoluenesulfonyl)-piperidine (3) with theGrignard reagent (4) is preferably carried out in the presence of aninert organic solvent, such as benzene, at temperatures between 50 and100 C. Subsequently, the resulting magnesiumcomplex compound isdecomposed with water in the presence of ammonium chloride.

The hydrolysis of the N-(p-toluenesulfonyl) group, the imino group andthe alkoxy group in compound (5) is accomplished in the customary mannerand preferably in a single reaction step, for instance by refluxingcompound (5) in the presence of a customary ether-splitting agent, suchas concentrated hydrogen bromide or hydrogen iodide, and mostadvantageously in the presence of phenol.

METHOD B Reaction of a m-alkoxy-cyanide of Formula 1 above in thepresence of a basic condensation agent with a tertiarybis-(fi-halo-ethyl)-amine of the formula to form the correspondingN-cinnamyl-4-cyano 4 (malkoxy-phenyl) piperidine of the formula alkyl-OGEN Compound IV is then reacted with a Grignard reagent of the Formula 4above and with water and ammonium chloride to form the correspondingketimine compound of the formula which is then subjected to acidhydrolysis to hydrolize the ketimine group and the alkoxy group and formthe desired end product of the Formula I above.

The alkaline condensation reaction between Compound I and Compound IIIis preferably carried out in the presence of sodium amide as the basiccondensation agent, and in the presence of an inert organic solvent attemperatures between 50 and 200 C. The subsequent Grignard reaction ispreferably also performed in the presence of an inert organic solvent,such as benzene, at temperatures between 50 C. and C. The magnesiumcomplex compound formed by the Grignard reaction is then decomposed withwater in the presence of ammonium chloride to yield the ketimine. Thefinal acid hydrolysis is carried out under customary conditions.

METHOD C Reaction of a 3-(3'-hydroxy-pheny1) 3 propionyl-1,5-dihalo-pentane of the formula l 0/ -C2Hu Cg CH2 JH CH l lal Hal (VI)in accordance with the following reaction formula (VII) O ii-C211 CH2NCHaCH=CH-C6H5 (II- z CH2 6H, C'H. l ial I IaI O -CzHi This reactionis performed under customary conditions, that is, preferably in thepresence of an inert organic solvent and of a basic condensation agent,such as sodium bicarbonate, or dimethylaniline, at temperatures between50 and 150 C.

The compound of the Formula I above may readily be converted into acidaddition salts, especially non-toxic, pharmacologically acceptable acidaddition salts, by customary methods, that is, by acidifying the freebase with the appropriate acid, preferably in the presence of an inertsolvent, such as ethanol. Typical examples of pharmacologicallyacceptable non-toxic acid addition salts of the present piperidinederivative are those formed with hydrochloric acid, hydrobromic acid,sulfuric acid, phosphoric acid, nitric acid, acetic acid, propionicacid, butyric acid, valeric acid, oxalic acid, malonic acid, succinicacid, maleic acid, fumaric acid, lactic acid, tartaric acid, citricacid, malic acid, benzoic acid, phthalic acid, cinnamic acid, salicylicacid, nicotinic acid, 2-furoic acid, 8-chlorotheophylline and the like.

The following example shall further illustrate the present invention andenable others skilled in the art to understand it more completely. Itshould be understood, however, that our invention is not limitedexclusively to this example.

EXAMPLE 1 Preparation of Ncinnamyl-4-(3'-hydroxyphenyl)-4-propionyl-piperidine and itshydrochloride and methanesulfonate by Method A Step a: Preparation of 1(p-toluene-sulfonyl)-4-(3'- methoxyphenyl) 4 cyano-piperidine.147.0 gm.(1.0 mol) of m methoxy-benzyl-cyanide and 196 gm. 1.0 mol) ofbis-(,B-chloroethyD-(p toluene-sulfonyD-amine were dissolved in 1500 cc.of absolute toluene in a 3-liter 3-neck flask provided with a stirrerand a thermometer. Thereafter, while continuously stirring the solution,83 gm. (2.13 mol) of finely powdered sodium amide were gradually addedat 40-45 C. A considerable amount of heat of reaction was evolved duringthe addition of the sodium amide, so that the flask had to be thoroughlycooled to maintain the desired temperature range. After all of thesodium amide had been added to reaction mixture was refluxed for onehour. Thereafter, the reaction mixture was cooled in an ice water bath,and when the temperature had reached 05 C. 120 cc. of Water were addeddropwise while stirring. Subsequently, an additional 1000 cc. of waterwere added all at one time while stirring, whereupon the reactionproduct precipitated out in practically pure, solid form. Theprecipitate was separated by vacuum filtration, washed with water,suspended 6 in 250 cc. of methanol, again vacuum filtered, washed with100 cc. of methanol and dried. 240 gm. (65% of theory) of crystallinel-(p-toluene-sulfonyl) 4 (3'-me thoxyphenyl)-4-cyano-piperidine of theformula CHaO GEN

I CH3 were obtained. The product had a melting point of 167 C.

Step b: Preparation of 4-[l-(p-toluene-sulfonyl)-4-(3'-methoxyphenyl)]-piperidyl-ethyl ketimine.A Grignard solution wasprepared in the customary manner from 374 gm. (2.4 mol) of ethyl iodideand 57.5 gm. (2.4 mol) of magnesium in 750 ml. of ether. The ether wasdistilled off in an atmosphere of nitrogen, and the residue wasdissolved in 750 cc. of absolute benzene. 222 gm. (0.6 mol) ofl-(p-toluene-sulfonyl) 4 (3 methoxyphenyl) 4 cyanopiperidine (theproduct obtained in Step a) were added to the resulting solution. Avirtually homogeneous solution was formed initially, but soon thereafterit became cloudy, accompanied by precipitation of a solid substance.This reaction mixture was then stirred on a water bath at C. for 16hours in a flask provided with a reflux cooler. The reaction mixture wasthen cooled on an ice water bath, and the cold reaction mixture wasstirred into a mixture of 3.5 kg. of crushed ice and 350 gm. of ammoniumchloride. Two liquid phases, that is, a benzene phase and an aqueousphase, formed after a short period of stirring. The benzene phase wasseparated with the aid of a separating funnel, and the remaining aqueousphase was extracted twice with about 500 cc. of benzene. The benzeneextract solutions were combined with the previously separated benzenephase, the combined solution was dried over sodium sulfate, and then thebenzene was evaporated in vacuo. About 246 gm. of the ketimine of theformula were obtained in the form of a honey-yellow syrup, whichcrystallized upon standing. This raw ketimine was used for the next stepof the synthesis without further purification.

Step c: Preparation of 4 (3' hydroxyphenyl)-4-propionyl-piperidine.-246gm. of the raw ketimine obtained in Step b were refluxed for three hourswith 1500 cc. of 48% hydrobromic acid and 246 gm. of phenol. Aftercooling, 1500 cc. of water were added to the reaction solution, and thenthe phenol was removed therefrom by extraction with ether. Thereafter,the light brown hydrogen bromide solution was concentrated byevaporation in vacuo, using a rotating evaporator. The evaporationresidue was triturated with acetone and the crystalline mass formedthereby was separated by vacuum filtration, washed with acetone anddried. 200 gm. of raw 4-(3'-hydroxyphenyl)-4-propionyl-piperidinehydrobromide were then freed from ammonium bromide and transformed intothe virtually pure free base in the following manner: The raw productwas dissolved in 400 cc. of water, the solution was treated withactivated charcoal, filtered and cooled to about 20 C. Thereafter, thesolution was admixed with 50 cc. of concentrated aqueous ammonia whilestirring, whereupon a solid precipitate formed. The precipitate wasseparated by vacuum filtration, washed with water and recrystallizedfrom ethanol. 97 gm. (70% of theory) of4-(3-hydroxyphenyl)-4-propionyl-piperidine of the formula O -CzHs wereobtained. The product had a melting point of 222 C.

Step d: Preparation of N-cinnamyl-4-(3'-hydroxyphenyl) 4propionyl-piperidine and its hydrochloride and methane sulfonate.0.01mol of 4-(3'-hydroxyphenyl)-4- propionyl-piperidine (the end product ofStep c) was refluxed for two hours with 1.26 gm. (0.015 mol) of sodiumbicarbonate and 2.15 gm. (0.011 mol) of cinnamyl bromide in the presenceof an inert organic solvent mixture consisting of cc. ofdimethylformamide and 25 cc. of tetrahydrofuran, accompanied bystirring. Thereafter, the solvent mixture was removed by evaporation,and the residue was washed from the reflux flask into a separatingfunnel with about 50 cc. of chloroform. Sub sequently, the chloroformicmixture was washed three times with 30 cc.-portions of water to removeinorganic salt impurities. The chloroform solution which remained wasdried over sodium sulfate and was then evaporated in vacuo. Theevaporation residue was recrystallized from a mixture of ethanol andether. N-cinnamyl4(3'-hydroxyphenyl)-4-propionyl-piperidine of theformula O -C2Hu CHz-CH=CH was obtained.

Upon treatment of the free base with ethanolic hydrochloric acid, 2 gm.(51.5% of theory) of the hydrochloride ofN-cinnamyl-4-(3'-hydroxyphenyl) 4 propionylpiperidine were obtained. Ithad a melting point of 228C.

Upon treatment of the free base with an equimolar amount ofmethane-sulfonic acid, the methane-sulfonate of N-cinnamyl 4(3'-hydroxyphenyl) 4 propionylpiperidine was obtained. It had a meltingpoint of 185- 189 C.

The piperidine compounds according to the present invention, that is,the compound embraced by Formula I above and its non-toxic acid additionsalts, have useful pharmacodynamic properties. More particularly, theyexhibit strong central analgesic activities in warm-blooded animals,such as mice, and, in addition, are free from physical dependencecapacity in rhesus monkeys.

The analgesic activity of the compounds accordingto the presentapplication was tested on adult white m1ce by the so-caled hot platemethod. Briefly stated, this test procedure involves subcutaneouslyinjecting varying doses of the compound to be tested into astatistically significant number of white mice and, after allowing theanalgesic activity to take effect, placing the treated mice on a hotplate maintained at an even temperature of about 55 C. After a certaintime interval the animals begin to feel the heat from the hot plate andgive way to a natural reflex by licking their paws. The time intervalbetween first contact with the hot plate and the onset of the naturalreflex phenomenon is accurately measured with a stop watch and iscompared with the corresponding time interval observed on untreatedcontrols. Analgesic activity of the compound being tested manifestsitself in a prolongation of the time interval between first contact andonset of the reflex phenomenon over the controls, and this prolongationis a direct measure of the degree of analgesic activity of the compoundin question at a given dosage. In the present case, the dosage of thecompound in question which prolonged the time interval by over thecontrols Was determined in terms of mgm.

per kg. body weight (ED The following results were obtained:

N-cinnamyl-4-(3'-hydroxyphenyl) 4 propionyl-piperidinemethanesulfonateED =1l mgm./ kg.

The tests which established the absence of physical dependence capacityin rhesus monkeys are described by G. A. Deneau and M. M. Seevers inBulletin, Drug Addiction and Narcotics, Volume 25, addendum 2, pp. 1-14, Jan. 29, 1962. I

For pharmaceutical purposes the compounds according to the presentinvention are administered to warmblooded animals perorally orparenterally as active ingredients in customary dosage unitcompositions, that is, compositions in dosage unit form consistingessentially of an inert pharmaceutical carrier and one effective dosageunit of the active ingredient, such as tablets, coated pills, capsules,wafers, powders, solutions, suspensions, emulsions, syrups,suppositories and the like. One effective dosage unit of the compoundsaccording to the present invention is from 0.415 to 1.67 mgm./kg. bodyweight, preferably 0.83 to 1.0 mgm./kg.

The following examples illustrate a few dosage unit compositionscomprising a compound of the instant invention as an active ingredientand represent the best mode contemplated of putting the invention topractical Ese. The parts are parts by weight unless otherwise speci-EXAMPLE 2 Hypodermic solution The solution was compounded from thefollowing ingredients:

Parts by vol. N-cinnamyl-4-(3-hydroxyphenyl) 4 propionylpiperidinemethanesulfonate 50.0 Hydroxyethyl-theophylline 70.0 Distilled waterQ.s. ad 1.0

Compounding procedure 9 EXAMPLE 3 Suppositories The suppositorycomposition was compounded from the following ingredients:

Parts N-cinnamyl-4-(3' hydroxyphenyl)-4-propionylpiperidinehydrochloride 60.0 Lactose 240.0 Cocoa butter 1400.0

Total 1700.0

Compounding procedure EXAMPLE 4 Tablets The tablet composition wascompounded from the following ingredients:

Parts N-cinnamyl-4-(3'-hydroxyphenyl) 4 propionylpiperidinemethanesulfonate 0.0 Lactose 90.0 Corn starch 40.0 Soluble starch 5.0Magnesium stearate 2.0 Colloidal silicic acid 3.0

Total 200.0

Compounding procedure The piperidine compound was admixed with thelactose and the corn starch, and the resulting mixture was moistenedwith an aqueous solution of the soluble starch. The moist mixture wasgranulated and dried. The dry granulate was uniformly admixed with themagnesium stearate and the colloidal silicic acid, and the resultingmixture was pressed into tablets weighing 200 mgm. each with the aid ofa conventional tablet making machine. Each tablet contained mgm. of thepiperidine compound and, when administered perorally to a warmbloodedanimal of about 60 kg. body weight in need of such treatment, producedvery good analgesic effects.

While We have illustrated our invention with the aid of certain specificembodiments, it will be readily apparent to others skilled in the artthat our invention is not limited to these embodiments and that variouschanges and modifications may be made without departing from the spiritof the invention or the scope of the appended claims.

We claim:

1. An analgesic composition comprising an analgesically effective amountof a compound selected from the group consisting ofN-cinnamyl-4-(3'-hydroxyphenyl)-4- propionyl-piperidine and a non-toxic,pharmaceutically acceptable acid addition salt thereof and an inertpharmaceutical carrier.

2. A method of relieving pain in a warm-blooded animal comprisingadministering to warm-blooded animals an analgesic amount of a compoundselected from the group consisting of N-cinnamyl-4-(3'-hydroxyphenyl)-4-propionyl-piperidine and a non-toxic, pharmaceutically acceptable acidaddition salt thereof.

3. The method of claim 2 wherein the active compound is administeredorally.

No references cited.

STANLEY J. FRIEDMAN, Primary Examiner U.S. Cl. X.R. 424-232, 253, 266

